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 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 505-510
 

Immunohistochemical expression of Bcl-2 in oral epithelial dysplasia and oral squamous cell carcinoma


1 Department of Oral Pathology, I.T.S. Centre for Dental Sciences and Research, Murad Nagar, Ghaziabad, Uttar Pradesh, India
2 Department of Oral Pathology, The Oxford Dental College and Hospital, Bangalore, Karnataka, India
3 Department of Oral Medicine and Radiology, D.J. College of Dental Sciences and Research, Niwari Road, Modinagar, Ghaziabad, Uttar Pradesh, India

Date of Web Publication10-Mar-2016

Correspondence Address:
S Juneja
Department of Oral Pathology, I.T.S. Centre for Dental Sciences and Research, Murad Nagar, Ghaziabad, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178411

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 » Abstract 


BACKGROUND: The B cell lymphoma-2 gene is a proto-oncogene whose protein product inhibits apoptosis. Its role is associated with keeping cells alive, but not by stimulating them to proliferation, as other proto-oncogenes do. Increased expression of protein product of Bcl-2 gene appears in the early phase of carcinogenesis leading to apoptosis impairment and in consequence to the progression of neoplastic changes. OBJECTIVE: To evaluate and compare the expression of Bcl-2 protein in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Sixty cases of formalin-fixed paraffin-embedded archival specimens comprising of 30 cases of leukoplakia with oral epithelial dysplasia and 30 cases of OSCC were taken for immunohistochemical analysis using monoclonal antibody against anti-human Bcl-2 oncoprotein. RESULTS: Immunostaining for Bcl-2 protein was identified in basal and parabasal layers as granular cytoplasmic staining in oral epithelial dysplasia. In OSCC, Bcl-2 immunoreactivity was most prominent in the peripheral cells of the infiltrating tumor islands which diminished toward the center in well-differentiated and moderately differentiated OSCC, whereas stronger and more diffuse expression of Bcl-2 oncoprotein was seen in poorly differentiated OSCC. Overall positivity of 26.7% (8/30) was observed in oral epithelial dysplasia and 30% (9/30) in OSCC in this study. INTERPRETATION AND CONCLUSION: Altered expression of Bcl-2 oncoprotein may be an early molecular event which leads to prolonged cell survival, increased chances of accumulation of genetic alterations, and subsequent increase in malignant transformation potential.


Keywords: Bcl-2, immunohistochemistry, oral epithelial dysplasia, oral squamous cell carcinoma


How to cite this article:
Juneja S, Chaitanya N B, Agarwal M. Immunohistochemical expression of Bcl-2 in oral epithelial dysplasia and oral squamous cell carcinoma. Indian J Cancer 2015;52:505-10

How to cite this URL:
Juneja S, Chaitanya N B, Agarwal M. Immunohistochemical expression of Bcl-2 in oral epithelial dysplasia and oral squamous cell carcinoma. Indian J Cancer [serial online] 2015 [cited 2019 Dec 16];52:505-10. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/505/178411





 » Introduction Top


Oral cancer is one of the most common cancer in the world and constitutes a major health problem in developing countries, representing the leading cause of death.[1] According to the World Health Organization (WHO), oral squamous cell carcinoma (OSCC) is the eighth most common cancer worldwide, with geographical variations.[2] In India, oral cavity cancers are the most common cancers in males and the third most common in females.[3] On the basis of a cancer registry, it is estimated that annually 75,000-80,000 new cases are reported in India, with an incidence rate of 12% of all cancers in men and 8% of all cancers among women.[4] The high incidence of oral cancer and pre-cancerous lesions in India has long been linked to the chronic use of tobacco in interesting forms such as reverse smoking and incorporating tobacco in betel quid, besides smoking tobacco.[5] Oral leukoplakia is the most common potentially malignant disorder of the oral cavity, which can precede OSCC.[6] The estimated reported prevalence of oral leukoplakia, worldwide, is approximately 2%. However, when viewed in relation to an annual malignant transformation rate of 1%, this prevalence figure would result in development of oral cancer in 20 per 100,000 populations per year.[7] Histopathologically, oral epithelial dysplasia currently is the most important prognostic indicator for determining the malignant transformation risk of oral leukoplakia. The oral leukoplakias have been reported to show an increased risk of conversion to malignant transformation varying from 0.13% to 6%, and the risk further increased to 14% or higher in dysplastic lesions.[8]

A characteristic feature of cancer cells is their immortality. Although normal cells undergo a steady progression from cell division through maturity, differentiation, senescence, and death, cancer cells continue to divide and survive without limit.[9] Apoptosis means programmed cell death. Cancer occurs when mutation affects the control mechanisms of apoptosis and cell survival.[10] This mechanism is regulated by several sets of genes, the best characterized of which are the Bcl-2 family which consists of both pro- and anti-apoptotic members, which all share sequence homology in their Bcl-2 homology domains.[11] Bcl-2 is a proto-oncogene originally described in human follicular non-Hodgkin's B-cell lymphomas.[12] The Bcl-2 proto-oncogene product is a 26-kDa protein which is a component of the nuclear envelope, endoplasmic reticulum, and the outer mitochondrial membrane, encoded in chromosome 18q21.,[13],[14] Bcl-2, through extended cell survival, can facilitate the acquisition of additional mutations in other tumor suppressor genes and oncogenes, which cumulatively results in clonal progression.[15]

In view of oral epithelial dysplasia as precursors of OSCCs and its potential malignant behavior, the purpose of this study was to evaluate and compare Bcl-2 protein expression in oral epithelial dysplasia and OSCC of varying grades.


 » Materials and Methods Top


Sixty formalin-fixed paraffin-embedded specimens of previously diagnosed cases of oral epithelial dysplasia (30 cases) and OSCC (30 cases) were retrieved from the archives. All the cases of oral epithelial dysplasia were selected based on the definition given by WHO working group (2007) and OSCC were selected based on the criteria given by WHO (2005).[6],[16]

Oral epithelial dysplasia (n = 30) comprised of 10 cases each of leukoplakia with mild epithelial dysplasia, moderate epithelial dysplasia, and severe epithelial dysplasia. OSCC (n = 30) comprised of 11 cases of well-differentiated OSCC, 10 cases of moderately differentiated OSCC, and 9 cases of poorly differentiated OSCC. Sections of tonsils served as positive controls, whereas lymphocytes within the lesional connective tissue served as internal positive controls.

Sections of 4 μm thickness were taken on to pre-coated silanized slides for immunohistochemistry and were incubated at 37°C overnight prior to immunostaining. Peroxidase block followed by heat-induced epitope retrieval using microwave oven method was used for antigen retrieval using Tris EDTA buffer at pH 9. Protein block was followed by primary and post-primary blocks followed by application of secondary antibody. DAB (3, 3 diamoino benzidine chromogen solution) was used as substrate chromogen. Mayer's hematoxylin was used as a counterstain. Tonsillar tissues served as positive controls.

The percentage of positive cells was counted by single observer and classified as: More than 50% of cells positive (+++); 25-50%: Positive (++); 5-24% positive (+), and fewer than 5% positive or no staining (–).

Statistical analyses were performed using the Statistical Package for Social Science (SPSS v 10.5) software. The proportions were compared using Chi-square test of significance.


 » Results Top


The mean age distribution in leukoplakia with oral epithelial dysplasia was 46 years and in OSCC was 61 years. In oral epithelial dysplasia patients, out of 30 cases, 16 were males and 14 were females. In OSCC, out of 30 cases, 15 were males and 15 were females. Out of 30 cases of oral leukoplakia, the total positivity for Bcl-2 was seen in 26.7% (8/30) cases and among 30 cases of OSCC, the total positivity for Bcl-2 expression was seen in 30.0% (9/30) cases. On evaluation of intensity of Bcl-2 expression in 30 cases of oral leukoplakia, none (0/30) of the cases showed >50% positivity, 10.0% (3/30) cases showed 25-50% positivity, and 16.7% (5/30) cases showed 5-25% positivity and 73.3% (22/30) cases showed complete negative expression for Bcl-2. In OSCC, 3.3% (1/30) cases showed >50% positivity, 10.0% (3/30) cases showed 25-50% positivity, and 16.67% (5/30) cases showed 5-25% positivity and 70.0% (21/30) cases showed complete negative expression for Bcl-2 [Figure 1] and [Figure 2].
Figure 1: Comparison of intensity of Bcl-2 expression in oral epithelial dysplasia patients

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Figure 2: Comparison of intensity of Bcl-2 expression in oral squamous cell carcinoma patients

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In sections of positive controls, most of the interfollicular and almost all mantle zone lymphocytes showed strong cytoplasmic immunostaining for Bcl-2 protein with only a few positive cells seen within the lymphoid follicles. In oral epithelial dysplasia cases, immunostaining for Bcl-2 protein was identified in basal keratinocytes and parabasal layer of cells as granular cytoplasmic staining in different histological grades [Figure 3]. The distribution of Bcl-2 immunoreactivity staining in OSCC cases showed most prominent expression in the peripheral cells of the infiltrating tumor islands which diminished toward the center of the island in well-differentiated OSCC and moderately differentiated OSCC [Figure 4] and positivity in dysplastic squamous cells in poorly differentiated OSCC [Figure 5].
Figure 3: Bcl-2 positivity in basal and parabasal layers in mild epithelial dysplasia (×100)

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Figure 4: Bcl-2 positivity in peripheral cells and diminishing toward the center of the epithelial islands in well-differentiated squamous cell carcinoma (×400)

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Figure 5: Bcl-2 positivity in poorly differentiated squamous cell

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No statistically significant differences between the expression Bcl-2 in oral leukoplakia and OSCCwere observed (P > 0.05). However, increased expression of Bcl-2 in OSCC as compared to oral leukoplakia may be an evidence of the disease progression of oral leukoplakia to OSCC, as the results of this study suggest alterations in expression of Bcl-2 protein, creating a favorable environment for malignant transformation.


 » Discussion Top


Carcinogenesis of OSCC is a multistage process involving the activation of oncogenes and inactivation of tumor suppressor genes with imbalance of cell death and growth, while considerable interest has recently been focused on the identification of regulator of apoptosis that may be a potential and key influence on the balance of cell death and cell growth in cancer.[17]

Transformation of normal epithelium to neoplastic epithelium is the result of a series of genetic mutations, leading to progressive loss of the mechanisms of cell control and apoptosis and consequently, alterations in cell differentiation.[18] The expression and function of apoptosis regulating genes are under complex regulatory mechanisms including transcriptional control and translational modifications.[19]

Bcl-2 gene derives its name from follicular B-cell lymphoma in which the chromosome translocation t (14;18) was first identified by molecular analysis. The Bcl-2 family is divided into two groups; anti-apoptotic proteins, such as Bcl-2 and Bcl-xL and pro-apoptotic proteins, such as bax and bak. Members of the Bcl-2 gene family may exist as alternatively spliced variants, such as Bcl-2α and -β messenger RNA.[20] The increased expression of Bcl-2 makes the removal of genetically modified cells difficult, favoring the accumulation of new mutations, which can result in the appearance of cells with malignant phenotype. Bcl-2 has the capacity of interrupting the apoptosis process both in the initial and final phases because this protein not only stabilizes the potential of the mitochondria membrane when forming heterodimers with bax but also inhibits the formation of oxygen-reactive species and intracellular acidification.[21]

In many earlier studies, overexpression of Bcl-2 protein has been demonstrated in carcinomas of the nasopharynx, lung, colorectum, prostate, stomach, and esophagus. In addition, overexpression has also been observed in pre-cancerous lesions of the colorectum, oral cavity, stomach, and esophagus. This suggests that Bcl-2 may be associated with early oncogenesis in these organs.[22]

The increased expression of Bcl-2 not only is essential to oral carcinogenesis [15],[20] but also influences the progression of the disease because it increases the survival rate of neoplastic cells, allowing new genetic mutation to occur and granting them higher resistance to chemotherapy and radiotherapy.[18]

In various studies conducted on oral tissues, overexpression of Bcl-2 was reported in oral dysplastic lesions and was suggested to play an important role in oral tumorigenesis.,[23],[24],[25],[26] Few other studies have reported a sporadic Bcl-2 expression or lack of expression in oral dysplasias.[27],[28] These reports suggest that dysregulation of the Bcl-2 gene may be one of many genetic aberrations in the progression of epithelial tumors.[20]

Hence, this study was undertaken to investigate the role of Bcl-2 in oral epithelial dysplasia and OSCC. The results of this study demonstrated that Bcl-2 oncoprotein is observed as cytoplasmic granular staining which is in accordance with previous observations of Singh et al.,[25] Yao et al.,[26] Loro et al.,[29] and Solomon et al.[5]

This study comprised of 30 cases of oral epithelial dysplasia, in which overall positivity of 26.7% (8/30) cases was observed. Other studies which have assessed Bcl-2 oncoprotein in histologically proven cases of dysplasia have shown variable results for positive Bcl-2 immunoexpression ranging from 12-19% by Ravi et al.[23] to 37% by Singh et al.[25]

In our study, it was observed that 20% (2/10) cases of mild dysplasia, 20% (2/10) cases of moderate dysplasia, and 40% (4/10) cases of severe dysplasia showed positivity for Bcl-2 expression, thus showing a progressive increase in Bcl-2 expression from mild and moderate epithelial dysplasia to severe epithelial dysplasia. Singh et al.[25] also attempted to correlate the level of Bcl-2 expression in various grades of dysplasia. They noted a positivity of 25% in mild dysplasia, 32% in moderate dysplasia, and 56% in severe dysplasia and they also found a proportional increase in Bcl-2 oncoprotein in all categories of dysplasia.

In this study which comprised of 30 cases of OSCC, the total positivity was seen to be 30% (9/30) of all the OSCC cases. In such previous studies, variable results have been shown in relation to Bcl-2 oncoprotein expression in OSCC ranging from 16.67% to 25% by Singh et al.,[25] 36.1% by Piatelli et al.,[30] 50% by Yao et al.,[26] 60% by Jordan et al.,[24] 83.3% by Solomon et al.[5] to 86.8% by Camisasca et al.[31]

Studies in Indian OSCC have also shown positive expression of Bcl-2 oncoprotein varying from 17.9% by Saikrishana et al.,[32] 23% by Kannan et al.,[15] and 56% by Teni et al.[8] The differences in Bcl-2 expression from various studies may reflect subtle inherent differences in upstream genetic events between the different population groups, as also the environmental differences.[8]

We also observed an increased Bcl-2 expression in the cytoplasm of basal cells of dysplastic epithelium adjacent to the tumor epithelium which is in accordance with the observation of Yao et al.,[26] Chen Yu et al.,[22] and Kummoona et al.[10] This observation raises the possibility that Bcl-2 alteration may precede early invasive tumor development.

The cells peripherally located within infiltrating tumor nests were more intensely stained, while fully keratinized neoplastic cells showed diminished or absence of Bcl-2 immunoreactivity in OSCC cases. Similar results were observed by Chen Yu et al.,[22] Piatelli et al.,[30] Sulkowska et al.,[33] Kummoona et al.,[10] and Camisasca et al.[31] These observations might be attributed to down-regulation of Bcl-2 expression concomitant with terminal cell differentiation (keratinization).[25]

Stronger expression of Bcl-2 oncoprotein was seen in poorly differentiated OSCC which is consistent with the findings of Chen Yu et al.[22] and Sulkowska et al.[33] The increased Bcl-2 expression in poorly differentiated carcinomas may reflect the loss of ability of malignant keratinocytes to differentiate terminally. Bcl-2 has previously been seen to actively block the differentiation of cultured keratinocytes in an in vitro experiment as well.[34]

Tonsillar tissue was taken as positive control which has been validated previously by Singh et al.[25] and Loro et al.[29] Normal lymphocytes present in the tissues represented an internal positive control for Bcl-2 immunostaining which showed strong positivity for Bcl-2 oncoprotein. These observations are in accordance with Teni et al.,[8] Loro et al.,[29] and Piatelli et al.[31]

No statistically significant differences between the expression Bcl-2 in oral epithelial dysplasia and OSCC were observed. However, increased expression of Bcl-2 in OSCC as compared to oral epithelial dysplasia may be an evidence of the disease progression of oral epithelial dysplasia to OSCC, as the results of this study suggest alterations in expression of Bcl-2 protein, creating a favorable environment for malignant transformation.

Overall discrepant results have been obtained so far in the studies dealing with Bcl-2 immunoreactivity in OSCC and oral epithelial dysplasia. Some of them have shown enhanced Bcl-2 expression and others have demonstrated reduced expression in tumor cells in comparison with the adjacent normal mucosa.[10] The differences in immunolocalization of Bcl-2 in various epithelia and neoplastic tissues may be topographical in nature or as a result of different laboratory protocols and antibodies used in the different studies. The latter is likely to be the case, particularly where conflicting data exist on the same tissue.[29]

The contradictory results concerning prognosis and expression of Bcl-2 oncoprotein in previous studies indicate that induction of apoptosis is very complex and the influence of individual proteins may vary from tumor to tumor. It is also important to note that it is the balance between anti- and pro-apoptotic proteins that determine the fate of the cell. It is important to note that these proteins can be diversely regulated by post-translational modifications, such as phosphorylation or proteolytic cleavage, and also the balance between apoptotic and survival signaling pathways may be the result of apoptosis-regulating microRNAs.[2]

Most studies on Bcl-2 have been conducted on formalin-fixed, paraffin-embedded tissue sections. Fixation and antigen retrieval methods such as enzyme digestion, microwave treatment or a combination of both are found to affect the sensitivity of the antibodies used.[28],[29]

Variations in expression patterns of Bcl-2 could also be related to alternate mRNA splicing of the expressed Bcl-2 protein in various cancers. It is known that isoforms of the Bcl-2 protein exist in human tissue and in cell lines. Alternatively, differences in Bcl-2 expression patterns, detectable by Bcl-2 antibodies, could be explained by elective caspase activation resulting in proteolytic degradation of Bcl-2 in tumor cells. It is worth speculating whether potential isoforms of Bcl-2 or cleaved variants might affect the sensitivity and specificity of the available Bcl-2 antibodies.[29]

All these studies represent samples from varying intraoral sites in various populations with variable exposure to risk factors. The type of positive and negative controls used is unclear in some cases, all of which might account for the disparity with the current findings.[28]

It is always possible that there is variation in Bcl-2 immunoreactivity between studies due to the type of antibody used as demonstrated by Loro et al.[29] However, these results should be viewed with caution as it is uncertain as to how the antibodies in question are raised. Competitive assays, where different antibodies compete against the same recombinant protein to confirm specificity in the immunohistological context, are only valid if all are raised against the same recombinant protein.[28]


 » Conclusion Top


The identification of molecular markers may provide a useful insight into the potential behavior or aggressiveness of tumors which is an essential step for the improvement of cancer treatment and prognosis. The results of this study indicate that the Bcl-2 gene product may play an important role in cellular decision making. However, its role is less clear in terms of progression of carcinogenesis as it is known that the interaction among various members of the Bcl-2 protein family can control the sensitivity or resistance of cells to apoptosis. The evaluation of expression of Bcl-2 may provide a better understanding of the biological behavior of oral dysplastic and cancerous lesions which, in the future, may have important therapeutic and prognostic implications with better understanding of the molecules that control cell survival and apoptosis.


 » Acknowledgement Top


The authors would like to acknowledge Dr. Vijaya Mysorekar, Professor, Department Of Pathology, M.S. Ramaiah Medical College, Bangalore, India. The authors would also like to acknowledge Colgate Palmolive India Pvt. Ltd. for supporting the study.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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